One of the goals of the Regulatory Science program within the Common Fund is to develop innovative in vitro models of complex tissues to facilitate evaluation of new drugs in a rapid manner. In this proposal, we will develop a 3D model of skin using iPSCs that have been differentiated to form keratinocytes and fibroblasts, for the first time Our lab has led the field in the development of differentiation protocols to form keratinocytes from human iPSC, and we are currently doing the same for dermal fibroblasts. In addition, we will develop a contextual model of a representative complex human skin diseases, psoriasis, by generating patient-specific iPSC from psoriatic lesions as the basis for the constructs. These constructs will also incorporate different populations of immune cells, such as Th17 cells, with the goal of modeling the inflammatory component of the disease as well as the skin barrier component. Lastly, in order to model both topical and systemic drug delivery for skin diseases, we will incorporate perfusable microvascular networks within the skin equivalents, which can be infused with selected therapeutic agents. Currently, there are no reliable in vitro models by which the efficacy and safety of psoriasis drug candidates can be tested, and this represents a major unmet pharmaceutical need. In this proposal, we will use microbiofabrication techniques to produce skin equivalents that better mimic systemic drug delivery to the skin, by incorporating perfusable microvascular networks within the skin equivalents. Our iPSC-derived constructs will represent a significant advance over currently available models. Current skin models comprise of fibroblasts seeded either in a collagen gel, or into a scaffold with keratinocytes seeded on top There have been several adaptations of these models in recent years, for example, pigmented models have been developed by incorporation of melanocytes, which can be used to assess product efficacy for solar protection. Immunocompetent skin models have been established containing Langerhans and dendritic cells with which pharmaceutical companies can evaluate allergenic or sensitizing agents. In all of these models, the cells used to comprise the equivalent are obtained directly from donor skin, and as such, these constructs require large amounts of input cells, and are often limited by the size of the original biopsy. Within this proposal we aim o establish a skin construct composed entirely of fibroblasts and keratinocytes derived from induced pluripotent stem cells (iPSCs), to produce an unlimited supply of disease- specific donor cells for use in skin constructs, which can be differentiated into multiple cell lineages. More broadly, this platform can be expanded to generate models other complex skin disorders for which new therapeutic options are in great demand. PUBLIC HEALTH RELEVANCE: One of the goals of the Regulatory Science program within the Common Fund is to develop innovative in vitro models of complex tissues to facilitate evaluation of new drugs in a rapid manner. In this proposal, we will develop a 3D model of skin using iPSCs that have been differentiated to form keratinocytes and fibroblasts, for the first time Our lab has led the field in the development of differentiation protocols to form keratinocytes from human iPSC, and we are currently doing the same for dermal fibroblasts. In addition, we will develop a contextual model of a representative complex human skin diseases, psoriasis, by generating patient-specific iPSC from psoriatic lesions as the basis for the constructs. These constructs will also incorporate different populations of immune cells, such as Th17 cells, with the goal of modeling the inflammatory component of the disease as well as the skin barrier component. Lastly, in order to model both topical and systemic drug delivery for skin diseases, we will incorporate perfusable microvascular networks within the skin equivalents, which can be infused with selected therapeutic agents. This proposal is highly responsive to the goals of the Regulatory Science program.